The invention relates to novel phenanthridine-N-oxides, which are used in the pharmaceutical industry for the production of medicaments.
Chem. Ber. 1939, 72, 675-677, J. Chem. Soc., 1956, 4280-4283 and J. Chem. Soc. (C), 1971, 1805 describe the synthesis of 6-phenylphenanthridines. The International Applications WO 97/28131 and WO 97/35854 describe 6-phenyl- and 6-pyridylphenanthridines as PDE4 inhibitors.
It has now been found that the novel N-oxides of substituted 6-phenylphenanthridines described in greater detail below have surprising and particularly advantageous properties.
The invention thus relates to the N-oxides of the compounds of the formula I, 
in which
R1 is hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or completely or predominantly fluorine-substituted 1-4C-alkoxy,
R2 is hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or completely or predominantly fluorine-substituted 1-4C-alkoxy,
xe2x80x83or in which
R1 and R2 together are a 1-2C-alkylenedioxy group,
R3 is hydrogen or 1-4C-alkyl,
R31 is hydrogen or 1-4C-alkyl,
xe2x80x83or in which
R3 and R31 together are a 1-4C-alkylene group,
R4 is hydrogen or 1-4C-alkyl,
R5 is hydrogen,
R51 is hydrogen,
xe2x80x83or in which
R5 and R51 together represent an additional bond,
R6 is an R7- and R8-substituted phenyl radical, where
R7 is hydroxyl, halogen, cyano, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylcarbonyloxy, trifluoromethyl, phenyl, phenyl-14C-alkyl, nitro, amino, completely or predominantly fluorine-substituted 1-4C-alkoxy, SO2xe2x80x94R70 or N(R71)R72, where
R70 is 1-4C-alkyl,
R71 is hydrogen, 1-4C-alkyl, SO2xe2x80x94R9 or SO2xe2x80x94R10 and
R72 is 1-4C-alkyl, 1-4C-alkylcarbonyl or SO2xe2x80x94R10,
R8 is hydrogen, hydroxy, halogen, 1-4C-alkoxy or 1-4C-alkyl
xe2x80x83and where
R9 and R10 independently of one another are 1-4C-alkyl, phenyl, phenyl-1-4C-alkyl or phenyl which is substituted by one or more identical or different substituents, where the substituents are selected from the group consisting of nitro, 1-4C-alkyl, halogen, 1-4C-alkylcarbonylamino, 1-4C-alkoxy, completely or predominantly fluorine-substituted 1-4C-alkoxy, cyano, phenyl, naphthyl, trifluoromethyl or 1-4C-alkoxycarbonyl,
xe2x80x83and the salts of these N-oxides.
1-4C-Alkyl represents a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl and preferably the ethyl and methyl radicals.
1-4C-Alkoxy represents radicals which, in addition to the oxygen atom, contain a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy and preferably the ethoxy and methoxy radicals.
3-7C-Cycloalkoxy represents cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy, of which cyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred.
3-7C-Cycloalkylmethoxy represents cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy and cycloheptylmethoxy, of which cyclopropylmethoxy, cyclobutylmethoxy and cyclopentylmethoxy are preferred.
As completely or predominantly fluorine-substituted 1-4C-alkoxy, for example, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy, the 1,2,2-trifluoroethoxy, in particular the 1,1,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, the trifluoromethoxy and preferably the difluoromethoxy radicals may be mentioned. xe2x80x9cPredominantlyxe2x80x9d in this connection means that more than half of the hydrogen atoms are replaced by fluorine atoms.
1-2C-Alkylenedioxy represents, for example, the methylenedioxy [xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94] and the ethylenedioxy [xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94] radicals.
If R3 and R31 together have the meaning 1-4C-alkylene, the positions 1 and 4 in the N-oxides of the compounds of the formula I are linked to one another by a 1-4C-alkylene bridge, 1-4C-alkylene representing straight-chain or branched alkylene radicals having 1 to 4 carbon atoms. Examples which may be mentioned are the radicals methylene [xe2x80x94CH2xe2x80x94], ethylene [xe2x80x94CH2xe2x80x94CH2xe2x80x94], trimethylene [xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94], 1,2-dimethylethylene [xe2x80x94CH(CH3)xe2x80x94CH(CH3)xe2x80x94] and isopropylidene [xe2x80x94C(CH3)2xe2x80x94].
If R5 and R51 together are an additional bond, then the carbon atoms in positions 2 and 3 in the N-oxides of the compounds of the formula I are linked to one another via a double bond.
Halogen within the meaning of the invention is bromine, chlorine or fluorine.
1-4C-Alkylcarbonyloxy represents a carbonyloxy group to which one of the abovementioned 1-4C-alkyl radicals is bonded. An example which may be mentioned is the acetoxy radical [CH3C(O)xe2x80x94Oxe2x80x94].
Phenyl-1-4C-alkyl represents one of the abovementioned 1-4C-alkyl radicals which is substituted by a phenyl radical. Examples which may be mentioned are the benzyl radical and the phenethyl radical.
1-4C-Alkylcarbonyl represents a radical which, in addition to the carbonyl group, contains one of the abovementioned 1-4C-alkyl radicals. An example which may be mentioned is the acetyl radical.
1-4C-Alkylcarbonylamino represents an amino radical which is substituted by one of the abovementioned 1-4C-alkylcarbonyl radicals. An example which may be mentioned is the acetylamino radical [CH3C(O)xe2x80x94NHxe2x80x94].
1-4C-Alkoxycarbonyl represents a carbonyl group to which one of the abovementioned 1-4C-alkoxy radicals is bonded. Examples which may be mentioned are the methoxycarbonyl radical [CH3Oxe2x80x94C(O)xe2x80x94] and the ethoxycarbonyl radical [CH3CH2Oxe2x80x94C(O)xe2x80x94].
Exemplary R7- and R8-substituted phenyl radicals which may be mentioned are the radicals 4-acetamidophenyl, 3-acetamidophenyl, 4-acetoxyphenyl, 3-aminophenyl, 4-aminophenyl, 2-bromophenyl, 4-bromophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2-chloro-4-nitrophenyl, 4-diethylamino-2-methylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-chloro-5-nitrophenyl, 4-chloro-3-nitrophenyl, 2,6-dichlorophenyl, 3,5-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dibromophenyl, 2-cyanophenyl, 3-cyanophenyl, 4cyanophenyl, 4-diethylaminophenyl, 4-dimethylaminophenyl, 2-fluorophenyl, 4-fluorophenyl, 3-fluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 2-chloro-6-fluorophenyl, 2-fluoro-5-nitrophenyl, 2-hydroxyphenyl, 3-hydroxy-phenyl, 3,4-dichlorophenyl, 4-hydroxyphenyl, 4-hydroxy-3-methoxyphenyl, 2-hydroxy-4-methoxyphenyl, 2,4-dihydroxyphenyl, 2-methoxyphenyl, 2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2-dimethylaminophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-chloro-6-methylphenyl, 4-methyl-3-nitrophenyl, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 2,3-dimethylphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2,4-dinitrophenyl, 3,4-dinitrophenyl, 3,5-dinitrophenyl, 2,6-dinitrophenyl, 4-ethoxyphenyl, 2-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-(p-nitrophenylsulfonamido)phenyl, 3-(p-toluenesulfonamido)phenyl, 4-(p-toluenesulfonamido)phenyl, 4-(4ethylphenylsulfonamido)phenyl, 4-bis(p-toluenesulfonyl)aminophenyl, 4-bis(p-nitrophenylsulfonyl)aminophenyl, 3-(p-nitrophenylsulfonamido)phenyl, (N-acetyl-4-p-toluenesulfonamido)phenyl, 4-(benzylsulfonamido)phenyl, 3-(benzylsulfonamido)phenyl, 4-(methylsulfonamido)phenyl, 3-(methylsulfonamido)phenyl, 4-(N-methylmethylsulfonamido)phenyl, 3-(N-methylmethylsulfonamido)phenyl, 4-(3,4-dichlorophenylsulfonamido)phenyl, 3-(3,4-dichlorophenylsulfonamido)phenyl, 4-(3-nitrophenylsulfonamido)phenyl, 3-(3-nitrophenylsulfonamido)phenyl, 4-(4-bromophenyisulfonamido)phenyl, 3-(4-bromophenyisulfonamido)phenyl, 4-(3-bromophenylsulfonamido)phenyl, 3-(3-bromophenylsulfonamido)phenyl, 4-(3-fluorophenylsulfonamido)phenyl, 3-(3-fluorophenylsulfonamido)phenyl, 4-(4-fluorophenylsulfonamido)phenyl, 3-(4-fluorophenylsulfonamido)phenyl, 4-(4-chlorophenyisulfonamido)phenyl, 3-(4-chlorophenylsulfonamido)phenyl, 4-(3-chlorophenylsulfonamido)phenyl, 3-(3-chlorophenylsulfonamido)phenyl, 4-(4-acetylaminophenylsulfonamido)phenyl, 3-(4-acetylaminophenylsulfonamido)phenyl, 4-(4-methoxyphenylsulfonamido)phenyl, 3-(4-methoxyphenylsulfonamido)phenyl, 4-(3-trifluoromethylphenylsulfonamido)phenyl, 3-(3-trifluoromethylphenylsulfonamido)phenyl, 4-(4-trifluoromethylphenylsulfonamido)phenyl, 3-(4-trifluoromethylphenylsulfonamido)phenyl, 4-(4-trifluoromethoxyphenylsulfonamido)phenyl, 3-(4-trifluoromethoxyphenylsulfonamido)phenyl, 4-(3-methylphenyisulfonamido)phenyl, 3-(3-methylphenylsulfonamido)phenyl, 4-(3,4-dimethoxyphenylsulfonamido)phenyl, 3-(3,4-dimethoxyphenylsulfonamido)phenyl, 4-(4-cyanophenylsulfonamido)phenyl, 3-(4-cyanophenylsulfonamido)phenyl, 4-(3-cyanophenylsulfonamido)phenyl, 3-(3-cyanophenylsulfonamido)phenyl, 4-(3-chloro-4-methylphenylsulfonamido)phenyl, 3-(3-chloro-4-methylphenylsulfonamido)phenyl, 4-(4-biphenylsulfonamido)phenyl, 3-(4-biphenylsulfonamido)phenyl, 4-(4-isopropylphenylsulfonamido)phenyl, 3-(4-isopropylphenylsulfonamido)phenyl, 4-(naphth-1-ylsulfonamido)phenyl, 3-(naphth-1-ylsulfonamido)phenyl, 4-(naphth-2-ylsulfonamido)phenyl, 3-(naphth-2-ylsulfonamido)phenyl, 4-benzylphenyl, 4-biphenyl, 4-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 2-trifluoromethoxyphenyl, 4-methanesulfonylphenyl, 3-methanesulfonylphenyl, 2-methanesulfonylphenyl, 4-(4-methoxycarbonylphenylsulfonamido)phenyl or (N-methyl-4-p-toluenesulfonamido)phenyl.
Possible salts for the N-oxides of the compounds of the formula Ixe2x80x94depending on substitutionxe2x80x94are all acid addition salts or all salts with bases. Particular mention may be made of the pharmacologically tolerable salts of the inorganic and organic acids and bases customarily used in pharmacy. Those suitable are, on the one hand, water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, it being possible to employ the acids in salt preparationxe2x80x94depending on whether a mono- or polybasic acid is concerned and depending on which salt is desiredxe2x80x94in an equimolar quantitative ratio or one differing therefrom.
On the other hand, salts with bases are also suitable. Examples of salts with bases which may be mentioned are alkali metal (lithium, sodium, potassium) or calcium, aluminum, magnesium, titanium, ammonium, meglumine or guanidinium salts, where here too the bases are employed in salt preparation in an equimolar quantitative ratio or one differing therefrom.
Pharmacologically intolerable salts which can initially be obtained, for example, as process products in the preparation of the compounds according to the invention on an industrial scale are converted into pharmacologically tolerable salts by processes known to the person skilled in the art.
It is known to the person skilled in the art that the N-oxides according to the invention and their salts, when they are isolated, for example, in crystalline form, can contain various amounts of solvents. The invention therefore also comprises all solvates and in particular all hydrates of the N-oxides according to the invention, and also all solvates and in particular all hydrates of the salts of the N-oxides according to the invention.
The N-oxides of the compounds of the formula I to be emphasized are those in which
R1 is 1-2C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy or completely or predominantly fluorine-substituted 1-2C-alkoxy,
R2 is 1-2C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy or completely or predominantly fluorine-substituted 1-2C-alkoxy,
R3 is hydrogen,
R31 is hydrogen,
R4 is hydrogen or 1-2C-alkyl,
R5 is hydrogen,
R51 is hydrogen,
xe2x80x83or in which
R5 and R51 together represent an additional bond,
R6 is an R7- and R8-substituted phenyl radical, where
R7 is hydroxyl, halogen, cyano, 1-4C-alkoxy, 1-4C-alkylcarbonyloxy, trifluoromethyl, phenyl, phenyl-1-4C-alkyl, nitro, amino, completely or predominantly fluorine-substituted 1-4C-alkoxy, SO2xe2x80x94R70 or N(R71)R72, where
R70 is 1-4C-alkyl,
R71 is hydrogen, 1-4C-alkyl, SO2xe2x80x94R9 or SO2xe2x80x94R10 and
R72 is 1-4C-alkyl, 14C-alkylcarbonyl or SO2xe2x80x94R10,
R8 is hydrogen, halogen or 1-4C-alkoxy
xe2x80x83and where
R9 and R10 independently of one another are 1-4C-alkyl, phenyl or phenyl substituted by a substituent, where the substituent is selected from the group consisting of nitro, 1-4C-alkyl, 1-4C-alkoxy, halogen, trifluoromethyl or 1-4C-alkoxycarbonyl,
xe2x80x83and the salts of these N-oxides.
The N-oxides of the compounds of the formula I particularly to be emphasized are those in which
R1 is 1-2C-alkoxy,
R2 is 1-2C-alkoxy,
R3, R31, R4, R5 and R51 are hydrogen,
R6 is an R7- and R8-substituted phenyl radical, where
R7 is hydroxyl, halogen, 1-4C-alkoxy, 1-4C-alkylcarbonyloxy, phenyl, phenyl-1-4C-alkyl, nitro, amino, SO2xe2x80x94R70 or N(R71)R72, where
R70 is 1-4C-alkyl,
R71 is hydrogen or SO2xe2x80x94R10 and
R72 is 1-4C-alkyl, 1-4C-alkylcarbonyl or SO2xe2x80x94R10,
R8 is hydrogen, halogen or 1-4C-alkoxy
xe2x80x83and where
R10 is phenyl substituted by a substituent, where the substituent is selected from the group consisting of nitro, 1-4C-alkyl or 1-4C-alkoxycarbonyl,
xe2x80x83and the salts of these N-oxides.
Preferred N-oxides of the compounds of the formula I are those in which
R1 is 1-2C-alkoxy,
R2 is 1-2C-alkoxy,
R3, R31, R4, R5 and R51 are hydrogen,
R6 is an R7- and R8-substituted phenyl radical, where
R7 is SO2xe2x80x94R70,
R70 is 1-4C-alkyl,
R8 is hydrogen.
xe2x80x83and the salts of these N-oxides.
The N-oxides of the compounds of the formula I are chiral compounds having chiral centers in positions 4a and 10b and, depending on the meaning of the substituents R3, R31, R4, R5 and R51, further chiral centers in the positions 1, 2, 3 and 4.
The invention therefore comprises all conceivable pure diastereomers and pure enantiomers and their mixtures in any mixing ratio, including the racemates. The N-oxides of the compounds of the formula I are preferred in which the hydrogen atoms in positions 4a and 10b are cis to one another. The pure cis enantiomers are particularly preferred here.
Particularly preferred in this connection are those N-oxides of the compounds of the formula I which in the positions 4a and 10b have the same absolute configuration as the compound (xe2x88x92)-cis-1,2-dimethoxy-4-(2-aminocyclohexyl)benzene which on its part can be employed as a starting material having the optical rotation [xcex1]D2=xe2x88x9258.5xc2x0 (c=1, ethanol).
The enantiomers can be separated in a manner known per se (for example by preparation and separation of appropriate diastereoisomeric compounds).
Preferably, an enantiomer separation is carried out at the stage of the starting compounds of the formula III 
for example by means of salt formation of the racemic compounds of the formula III with optically active carboxylic acids. Examples which may be mentioned in this connection are the enantiomeric forms of mandelic acid, tartaric acid, O,Oxe2x80x2-dibenzoyltartaric acid, camphoric acid, quinic acid, glutamic acid, malic acid, camphorsulfonic acid, 3-bromocamphorsulfonic acid, xcex1-methoxyphenylacetic acid, xcex1-methoxy-xcex1-trifluoromethylphenylacetic acid and 2-phenylpropionic acid. Alternatively, enantiomerically pure starting compounds of the formula III can also be prepared via asymmetric syntheses.
The N-oxides of the compounds of the formula I can be prepared, for example, by the process described below in greater detail.
The process comprises subjecting compounds of the formula I, 
in which R1, R2, R3, R31, R4, R5, R51 and R6 have the meanings indicated above, to an N-oxidation and, if desired, then converting the N-oxides of the compounds of the formula I obtained into their salts, or, if desired, then converting salts of the N-oxides of the compounds of the formula I obtained into the free compounds.
The N-oxidation is carried out in a manner familiar to the person skilled in the art, e.g. with the aid of hydrogen peroxide in methanol or with the aid of m-chloroperoxybenzoic acid in dichloromethane at room temperature. The person skilled in the art will be familiar on the basis of his/her expert knowledge with the reaction conditions which are specifically necessary for carrying out the N-oxidation.
Compounds of the formula 1, in which R1, R2, R3, R31, R4, R5, R51 and R6 have the meanings indicated above, can be prepared from the corresponding compounds of the formula 11 by a cyclocondensation reaction. 
The cyclocondensation is carried out in a manner known per se to the person skilled in the art, according to Bischler-Napieralski (e.g. as described in J. Chem. Soc., 1956, 4280-4282) in the presence of a suitable condensing agent, such as, for example, polyphosphoric acid, phosphorus pentachloride, phosphorus pentoxide or preferably phosphorus oxychloride, in a suitable inert solvent, e.g. in a chlorinated hydrocarbon such as chloroform, or in a cyclic hydrocarbon such as toluene or xylene, or another inert solvent such as acetonitrile, or without further solvent using an excess of condensing agent, preferably at elevated temperature, in particular at the boiling temperature of the solvent or condensing agent used.
Compounds of the formula II in which R1, R2, R3, R31, R4, R5, R51 and R6 have the meanings indicated above are accessible from the corresponding compounds of the formula III, in which R1, R2, R3, R31, R4, R5 and R51 have the meanings indicated above, by reaction with compounds of the formula R6-CO-X, in which R6 has the meanings indicated above and X represents a suitable leaving group, preferably a chlorine atom. For example, the acylation or benzoylation is carried out as described in the following examples or as in J. Chem. Soc. (C), 1971, 1805-1808.
Compounds of the formula R6-CO-X and compounds of the formula III are either known or can be prepared in a known manner.
The compounds of the formula III can be prepared, for example, from compounds of the formula IV, 
in which R1, R2, R3, R31, R4, R5 and R51 have the abovementioned meanings, by reduction of the nitro group.
The reduction is carried out in a manner known to the person skilled in the art, for example as described in J. Org. Chem. 1962, 27, 4426 or as described in the following examples.
The reduction can be carried out, for example, by catalytic hydrogenation, e.g. in the presence of Raney nickel, in a lower alcohol such as methanol or ethanol at room temperature and under normal or elevated pressure. If desired, a catalytic amount of an acid, such as, for example, hydrochloric acid, can be added to the solvent. Preferably, however, the reduction is carried out using metals such as zinc or iron with organic acids such as acetic acid or mineral acids such as hydrochloric acid.
The compounds of the formula III in which R1, R2, R3, R31 and R4 have the meanings indicated above and R5 and R51 together represent an additional bond can be prepared from the corresponding compounds of the formula IV by selective reduction of the nitro group in a manner known to the person skilled in the art, for example in the presence of Raney nickel in a lower alcohol as solvent using hydrazine hydrate as a hydrogen donor.
The compounds of the formula IV, in which R1, R2, R3, R31 and R4 have the meanings indicated above and R5 and R51 are hydrogen, are either known or can be prepared from corresponding compounds of the formula IV in which R5 and R51 together are an additional bond. The reaction can be carried out in a manner known to the person skilled in the art, preferably by hydrogenation in the presence of a catalyst, such as, for example, palladium on active carbon, e.g. as described in J. Chem. Soc. (C), 1971,1805-1808.
The compounds of the formula IV, in which R5 and R51 together are an additional bond, are either known or can be obtained by the reaction of compounds of the formula V, 
in which R1 and R2 have the meanings mentioned above, with compounds of the formula VI,
R3-CHxe2x95x90C(R4)-C(R4)=CH-R31xe2x80x83xe2x80x83(VI) 
in which R3, R31 and R4 have the meanings mentioned above.
Compounds of the formula IV in which R5 and R51 together are an additional bond and R3 and R31 together are a 1-4C-alkylene group can be obtained, for example, by reaction of cyclic compounds of the formula VI, in which R4 has the meanings indicated above and R3 and R31 together are a 1-4C-alkylene group [e.g. cyclohexa-1,3-diene, 2,3-dimethylcyclohexa-1,3-diene, cyclohepta-1,3-diene, 2,3-dimethylcyclohepta-1,3-diene or cycloocta-1,3-diene], with compounds of the formula V in which R1 and R2 have the meanings indicated above.
The cycloaddition is in this case carried out in a manner known to the person skilled in the art according to Diels-Alder, e.g. as described in J. Amer. Chem. Soc. 1957, 79, 6559 or in J. Org. Chem. 1952, 17, 581 or as described in the following examples.
Compounds of the formula IV obtained in the cycloaddition, in which the phenyl ring and the nitro group are trans to one another, can be converted in a manner known to the person skilled in the art into the corresponding cis compounds, e.g. as described in J. Amer. Chem. Soc. 1957, 79, 6559 or as described in the following examples.
The compounds of the formulae V and VI are either known or can be prepared in a known manner. The compounds of the formula V can be prepared, for example, in a manner known to the person skilled in the art from corresponding compounds of the formula VII as described, for example, in J. Chem. Soc. 1951, 2524 or in J. Org. Chem. 1944, 9, 170 or as described in the following examples.
The compounds of the formula VII, 
in which R1 and R2 have the meanings indicated above, are either known or can be prepared in a manner known to the person skilled in the art, as described, for example, in Ber. Dtsch. Chem. Ges. 1925, 58, 203.
It is moreover known to the person skilled in the art that if there are a number of reactive centers on a starting or intermediate compound it may be necessary to block one or more reactive centers temporarily by protective groups in order to allow a reaction to proceed specifically at the desired reaction center. A detailed description for the use of a large number of proven protective groups is found, for example, in T. W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991.
The isolation and purification of the substances according to the invention is carried out in a manner known per se, e.g. by distilling off the solvent in vacuo and recrystallizing the resulting residue from a suitable solvent or subjecting it to one of the customary purification methods, such as, for example, column chromatography on suitable support material.
Salts are obtained by dissolving the free compound in a suitable solvent (e.g. a ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, an ether, such as diethyl ether, tetradhydrofuran or dioxane, a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol such as ethanol or isopropanol) which contains the desired acid or base, or to which the desired acid or base is then added. The salts are obtained by filtering, reprecipitating, precipitating with a nonsolvent for the addition salt or by evaporating the solvent. Salts obtained can be converted by alkalization or by acidification into the free compounds, which in turn can be converted into salts. In this way, pharmacologically intolerable salts can be converted into pharmacologically tolerable salts.
The following examples serve to illustrate the invention further without restricting it. Likewise, further compounds of the formula 1, whose preparation is not explicitly described, can be prepared in an analogous manner or in a manner familiar per se to the person skilled in the art using customary process techniques.
In the examples, m.p stands for melting point, h for hour(s), RT for room temperature, EF for empirical formula, MW for molecular weight, calc. for calculated, fnd. for found. The N-oxide mentioned as example is a preferred subject of the invention.